Phase I pharmacokinetic and pharmacodynamic study of LAQ824, a hydroxamate histone deacetylase inhibitor with a heat shock protein-90 inhibitory profile, in patients with advanced solid tumors.
OBJECTIVE
To determine the safety, maximum tolerated dose, and pharmacokinetic-pharmacodynamic profile of a histone deacetylase inhibitor, LAQ824, in patients with advanced malignancy.


METHODS
LAQ824 was administered i.v. as a 3-h infusion on days 1, 2, and 3 every 21 days. Western blot assays of peripheral blood mononuclear cell lysates and tumor biopsies pretherapy and posttherapy evaluated target inhibition and effects on heat shock protein-90 (HSP90) client proteins and HSP72.


RESULTS
Thirty-nine patients (22 male; median age, 53 years; median Eastern Cooperative Oncology Group performance status 1) were treated at seven dose levels (mg/m(2)): 6 (3 patients), 12 (4 patients), 24 (4 patients), 36 (4 patients), 48 (4 patients), 72 (19 patients), and 100 (1 patient). Dose-escalation used a modified continual reassessment method. Dose-limiting toxicities were transaminitis, fatigue, atrial fibrillation, raised serum creatinine, and hyperbilirubinemia. A patient with pancreatic cancer treated at 100 mg/m(2) died on course one at day 18 with grade 3 hyperbilirubinemia and neutropenia, fever, and acute renal failure. The area under the plasma concentration curve increased proportionally with increasing dose; median terminal half-life ranged from 8 to 14 hours. Peripheral blood mononuclear cell lysates showed consistent accumulation of acetylated histones posttherapy from 24 mg/m(2); higher doses resulted in increased and longer duration of pharmacodynamic effect. Changes in HSP90 client protein and HSP72 levels consistent with HSP90 inhibition were observed at higher doses. No objective response was documented; 3 patients had stable disease lasting up to 14 months. Based on these data, future efficacy trials should evaluate doses ranging from 24 to 72 mg/m(2).


CONCLUSIONS
LAQ824 was well tolerated at doses that induced accumulation of histone acetylation, with higher doses inducing changes consistent with HSP90 inhibition.
de Bono
Johann S
JS
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research , Surrey, UK. jdebono@icr.ac.uk
Kristeleit
Rebecca
R
Tolcher
Anthony
A
Fong
Peter
P
Pacey
Simon
S
Karavasilis
Vasilios
V
Mita
Monica
M
Shaw
Heather
H
Workman
Paul
P
Kaye
Stan
S
Rowinsky
Eric K
EK
Aherne
Wynne
W
Atadja
Peter
P
Scott
Jeffrey W
JW
Patnaik
Amita
A
D000107:Acetylation; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D015331:Cohort Studies; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D011379:Prognosis; D015996:Survival Rate
D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C477361:LAQ824; D006655:Histone Deacetylases